Are You Confident of the Diagnosis?

Psoriasis is a chronic inflammatory skin disease process involving immune-mediated cutaneous inflammation and keratinocyte proliferation. The diagnosis is based upon a combination of both history and physical examination parameters. Typically, psoriasis is characterized by scaly, erythematous patches, papules, and plaques that are often pruritic and can be painful.

The disease is a chronic disease that can wax and wane in severity and is typically improved with treatment. Rarely, spontaneous remissions can occur. There are multiple subtypes, including psoriasis vulgaris, plaque type psoriasis, inverse psoriasis, guttate psoriasis, nail unit psoriasis, erythrodermic psoriasis, and pustular psoriasis. Given the acuity of psoriasis and certain therapeutic considerations, erythrodermic and pustular psoriasis are discussed separately in this chapter.

What you should be alert for in the history

If a patient has a known history of other types of psoriasis, that may help support the diagnosis of erythrodermic and/or pustular psoriasis.

Characteristic findings on physical examination

Erythrodermic psoriasis/pustular psoriasis can be an acute onset form of psoriasis or may develop acutely or gradually in a patient with underlying plaque psoriatic disease. This severe form of psoriasis has substantial morbidity and an increased risk of mortality compared with other forms of psoriasis. Characteristically, in the erythrodermic variant, there is generalized erythema covering almost the entire body with varying amounts of scale (Figure 1). Pustular psoriasis can involve varying amounts of the skin surface and is characterized by skin erythema with overlying pustules (Figure 2). Edema, hair loss, or nail dystrophy also may be present in both variants.

Figure 1.

Example of extensive pustular/erythodermic psoriasis.

Figure 2.

Example of pustular psoriasis.

These two forms of psoriasis can be associated with fever and malaise as well as chills, hypothermia, and fluid loss. In the acute form these patients should be evaluated and aggressively managed, as high output cardiac failure and insensible fluid loss can be significant.

Diagnosis confirmation

The differential diagnosis of erythrodermic psoriasis includes cutaneous T-cell lymphoma (CTCL), a severe drug reaction, or pityriasis rubra pilaris; with these entities, skin biopsy, laboratory examination looking for eosinophilia (present in drug reactions and CTCL, abnormal cells present in CTCL), and an extensive history looking for culprit medications are often necessary as history and physical examination alone cannot differentiate these entities.

Who is at Risk for Developing this Disease?

Psoriasis has been diagnosed in approximately 2.6% of individuals in the United States, which amounts to approximately 5 million adults with psoriasis. Peak onset of the disease is roughly bimodal, most often at ages 16 to 22 and then ages 57 to 60; however, the disease can occur at any age.

Erythrodermic psoriasis is an uncommon form of psoriasis, affecting 1% to 2.25% of patients with psoriasis and may occur at any age, although it is less common in the pediatric population. Pustular psoriasis is equally rare and has an average age of onset at 50 years; however, children ages 6 weeks to 10 years also can rarely be affected.

Risk factors ultimately resulting in the initial presentation of psoriasis or worsening of psoriasis are poorly understood. Koebnerization (or exacerbation from physical trauma to the skin, including sunburn), preceding streptococcal infection, HIV infection, certain medications (e.g. beta-blockers, lithium, chloroquine, ACE-inhibitors, terbinafine, indomethacin, and interferon-alpha; even TNF inhibitors have been associated with paradoxical worsening of psoriasis, including pustular psoriasis), cigarette smoking, alcohol consumption, and emotional stress have been cited to increase risk for developing or exacerbating disease.

Family history also may increase the risk for development of disease. Some families appear to have an autosomal dominant pattern of inheritance with varying penetrance, and studies of twin siblings have demonstrated concordant disease in approximately 65-70% of monozygotic twins and only 20-25% in dizygotic twins. However, the development of psoriasis is multifactorial, resulting from genetic and environmental factors and still poorly understood.

What Is the Cause of the Disease?

Etiology

The exact etiology and pathogenesis is unknown but immunologic, genetic, and environmental factors also are implicated in the development of the disease.

Pathophysiology

Psoriasis is a complex inflammatory skin condition with abnormal epidermal keratinocyte differentiation and hyperproliferation. This process appears to be immunologically driven and mediated primarily by T cells in the dermis.

In the complex model of disease, the interactions of antigen-presenting cells (APCs) with T cells, as well as cytokines, trigger an immune response. The APCs in the skin interact with T cells, and an unidentified antigen is presented to the T cells, and this interaction, along with multiple co-stimulatory signals, lead to T cell activation and the release of cytokines.

The reactivation of T cells in the skin, and the local effects of cytokines such as tumor necrosis factor, interleukin (IL)-1 beta, and IL10 lead to inflammation, cell-mediated immune responses, and epidermal hyperproliferation. In addition to IL12, IL23 has been recently identified as playing an important role in the establishment of chronic inflammation and in the development of a T helper (Th) cell subset that produces IL-17. IL-17A (main cytokine of Th17 cells) stimulates keratinocyte production of proinflammatory mediators and cytokines. Both the innate and adaptive immune system play a role in the continued chronic inflammation in psoriasis. This Th17 pathway is a source of investigation for new therapeutics in psoriasis. These Th17 cells and the IL12/23 pathway are important in the pathophysiology of psoriasis.

Population studies have demonstrated that the incidence of psoriasis is greater among first-degree and second-degree relatives of patients than among the general population. In addition, genetic mapping studies have identified multiple chromosomal loci linked to the development of disease. Psoriasis susceptibility (PSOR1) on chromosome 6, also known as the HLA-Cw6 allele, has been strongly associated with the development of psoriasis (up to 10-fold increase in risk in the Caucasian population) and associated with early onset disease. Other genetic loci (PSOR2-PSOR9) and HLA-B13, -B17 also have been associated with psoriasis. However, multifactorial inheritance mechanisms without a genetic component also have not been excluded.

Variants in the gene encoding the IL-23 receptor and in the untranslated region of the IL12B (p40) gene also have been identified as indicators of psoriasis risk. While this data is compelling for genetic mechanisms, environmental factors also are known to play a role. These environmental factors are outlined above.

Recently, homozygous and heterozygous mutations in IL36 receptor antagonist have been implicated in patients with generalized pustular psoriasis (up to 40% in Germany), implicating a role for this and IL-1 in the pathogenesis of pustular psoriasis. Identification of this pathway has allowed some patients to be successfully treated with Anakinra, a recombinant interleukin-1 receptor antagonist. This has been termed DITRA (Deficiency of the Interleukin-36 Receptor Antagonist).

Systemic Implications and Complications

There are several comorbidities and associated systemic disorders that have been demonstrated to be associated with psoriasis. In addition, erythrodermic and pustular psoriasis also carry morbidity when acute and severe in presentation.

Erythrodermic and pustular psoriasis

High-output congestive heart failure may occur with erythrodermic psoriasis in the setting of acute onset and systemic manifestations such as fever, chills, and malaise. These patients also are at increased risk of superinfection and subsequent sepsis, especially from Staphylococcus aureus. Fluid and electrolye imbalance and peripheral edema from negative nitrogen balance through protein loss because of skin exfoliation also can occur and should be treated. Patients with pustular disease also should be evaluated for hypocalcemia, as this may occur. Other potential complications include deep venous thrombosis andpulmonary embolism caused by inmobility.

For psoriasis in general:

Psoriatic arthritis

Psoriatic arthritis is an inflammatory seronegative spondyloarthropathy associated with psoriasis; at least 5% of patients with psoriasis will be affected with arthritis. The prevalence overall in the United States is thought to be estimated to be between 0.1% to 0.25%. On average, cutaneous manifestations may occur for 12 years before the development of joint symptoms. Symptoms can range from mild to severe arthritis and is characterized by morning stiffness, pain, swelling, and tenderness of the joints and surrounding ligaments: dactylitis and enthesitis. The spectrum of psoriatic arthritis ranges from peripheral to axial disease. Hands tend to be involved more frequently than feet.

Patients should be routinely questioned for symptoms of arthritis, and if positive, radiographic studies should be performed. Characteristic radiographic features of psoriatic arthritis include joint erosions, joint space narrowing, bony proliferation, osteolysis, including "pencil in cup" deformity, acro-osteolysis, ankylosis, spur formation, and spondylitis. The course of psoriatic arthritis is variable and unpredictable and can vary from mild and nondestructive to a severe, debilitating, erosive arthropathy. Because psoriatic arthritis can be destructive, disease modifying anti-rheumatic drugs (DMARDs) are necessary and referral and collaboration with rheumatology may be required.

Obesity/metabolic syndrome

The connection between obesity and psoriasis has been confirmed by multiple large studies. Metabolic syndrome is the combination of obesity, impaired glucose regulation, hypertension, hypertriglyceridemia, and reduced high density lipoprotein, which can lead to an increased risk for cardiovascular disease. The prevalence of metabolic syndrome in hospitalized patients with psoriasis is significantly elevated when compared to those patients without psoriasis. Some hypothesize that obesity may potentiate inflammation of psoriasis and facilitate the development of metabolic syndrome. All psoriatic patients should be counseled on diet, exercise, and management of these comorbidities, as this inflammatory state may be contributing to their disease and can lead to other significant morbidity and mortality.

Cardiovascular disease

There is an increased risk of cardiovascular disease, which is thought to be multifactorial. Often times, patients with psoriasis are overweight, have increased incidence of diabetes, increased incidence of hypertension, and hyperlipidemia. Patients have an increased incidence of myocardial infarction, which may be related to their underlying other comorbidities as well as the medications used to treat the psoriasis. However, after correcting for heart disease risk factors, psoriatic patients have a higher probability of myocardial infarction compared to non-affected individuals, and there appears to be an increased relative risk seen in younger patients with more severe psoriasis. Increased rates of depression in psoriatic patients also may lead to increased risk of cardiovascular disease.

All patients should be counseled that they are increased risk for cardiovascular disease and they should be advised to promote heart healthy behaviors. In fact, some academic centers have established multidisciplinary centers where patients can be evaluated and more extensively counseled for behavior modification and close monitoring for the development of cardiovascular disease.

Autoimmune diseases:

Inflammatory bowel disease: The incidence of Crohn's disease and ulcerative colitis has been reported to be 3.8 to 7.5 times greater in patients with psoriasis than in the general population. The individual susceptibility to all 3 of these diseases has been localized to a similar region of chromosome 16. Patients should have a complete review of symptoms for any abdominal pain, diarrhea, fevers, or blood in the stool. If any of these symptoms exist, then referral to gastroenterology is appropriate.

Multiple sclerosis: Multiple sclerosis has been shown to be linked to psoriasis with a study that demonstrated psoriasis is more likely to occur in families of patients with multiple sclerosis.

Psychiatric Illness

Mood disorders and lack of self-esteem are increased in patients with psoriasis. According to a telephone survey, 80% of respondents reported that psoriasis had a negative impact on their lives (self-esteem issues and depression). The prevalence of depression in patients with psoriasis can be up to 60%, and this depression can be severe enough to lead to thoughts of suicide.

The psychological and emotional burden of psoriasis can include not only poor self-esteem and depression, but also sexual dysfunction and anxiety. Some studies suggest that treatment of psoriasis may help with emotional disorders resulting from the disease. Clinicians need to consider the psychosocial aspects of disease, and if emotional symptoms warrant further help, then referral to a psychiatrist may be appropriate.

Personal behaviors

The emotional impact of psoriasis also may impact patient's personal behaviors.

Smoking: Multiple studies have demonstrated an increased prevalence of smoking among psoriatic patients. The increased risk for incident psoriasis applied to both current and past smokers. A study conducted in Utah demonstrated a 37% prevalence of smoking in psoriasis population vs 13% in general population of Utah. In one study, the majority of these patients began smoking prior to the development of psoriasis. However, the exact link between cigarette smoking and psoriasis has not been established.

Alcohol: An increase in the amount of alcohol ingested in psoriatic patients has been established. However, the role that alcohol consumption has in the development of psoriasis still remains uncertain. Alcohol abuse may reflect the underlying psychological burden of disease or may be associated with other associated behaviors. Regardless, excessive alcohol intake most likely negatively impacts mortality. All patients should be questioned regarding their social behaviors, and these issues should be addressed when caring for any psoriatic patient.

Treatment Options

Treatment optiions are summarized in
Table I.

Table I.

Treatment options for psoriasis: erythrodermic and postular variants

Topical Therapies

Systemic Medical Therapies

As adjunctive therapy:Corticosteroids with or without occlusionOther adjuvants (after acute episode):AnthralinCalcineurin inhibitors (Tacrolimus/pimecrolimus)Coal tarSalicylic acidTazaroteneVitamin D analogues (calcipotriene/calcipotriol)*Combination of above therapies also can be used

Optimal Therapeutic Approach for this Disease

For erythrodermic or pustular psoriasis, topical therapies can be used as adjunctive medications or very aggressively under occlusion with sauna suits. Medium potency topical steroids, moisturizers, wet dressings/wraps and supportive care are necessary in these patients. If the presentation is less acute, then they also may be considered as therapy. However, systemic therapies are often necessary to control disease.

Some questions to consider in deciding on therapy:

Does the patient have severe psoriasis, is it erythrodermic or does he/she have extensive pustular psoriasis? If yes, then consider cyclosporine as first line treatment with transition to alternate therapy; acitretin also may be a good choice for generalized erythrodermic or pustular psoriasis.

Is the erythrodermic or pustular psoriasis acute in onset, or is the patient experiencing a flare? If so, then fast acting agents such as cyclosporine or infliximab may be considered first line therapies.

Is the erythrodermic or pustular psoriasis more chronic in nature? If so, then methotrexate or acitretin also may be considered or appropriate first line agents.

Erythrodermic patients

For erythrodermic patients, first-line therapies include cyclosporine, infliximab, acitretin, and methotrexate. Cyclosporine or infliximab may be considered first line because of their rapid onset of action. For less acute disease or contraindications to cyclosporine or infliximab, then acitretin or methotrexate should be considered.

Second-line therapies include etanercept, adalimumab, ustekinumab, and combination therapies. Little data exist for etanercept. Limited data supporting the use of ustekinumab in severe, refractory cases of erythroderma has been reported with dramatic improvement in skin lesions in as early as 4 weeks. Less data/no data are available for adalimumab. Combination therapy as listed above also can be used with some success.

Avoid use of systemic glucocorticosteroids, as this can lead to rebound flares and worsening of underlying disease and should be avoided. Also avoid use of phototherapy, as this may cause additional erythema and pain and can be poorly tolerated.

The acuteness of the presentation of this type of psoriasis needs to be considered when choosing a systemic therapy so that medications with a more rapid onset are considered for disease when presentation is more acute, while medications that are slower to action can be considered for disease which has been present more chronically.

In some patients with generalized pustular psoriasis, including those with IL-36RN mutations, there are early reports describing the efficacy of anakinra, an IL-1 receptor antagonist. The standard dose is 100 mg subcutaneous daily. The average time to improvement in symptoms is 2-6 weeks.

Methotrexate may be used as solo therapy or in conjunction with tumor necrosis factor (TNF) TNF alpha inhibitors to prevent antibody formation to the biologic agents. Begin with an initial test dose of 2.5 or 5 mg once and then increase to 15-25 mg weekly as tolerated. Dosing can be oral, intramuscular (IM), or subcutaneous. Expect 3 months for full effect to be appreciated at optimal dose. Monitor baseline complete blood count (CBC), comprehensive metabolic panel (CMP), hepatitis B and C, HIV; follow-up with CBC and liver function test (LFT) every week for 2 weeks, then every 3-4 months.

With respect to liver biopsy, in patients with no risk factors, liver biopsy may not be needed. In those patients with risk factors, then earlier liver biopsy may be necessary. Delayed baseline liver biopsy after 2-6 months of therapy to establish medication efficacy and tolerability should be considered, with repeated liver biopsies after approximately 1 to 1.5 g of medication. Contraindications for methotrexate are pregnancy, renal impairment, hepatitis or cirrhosis, pulmonary fibrosis, alcohol use, leukemia, and thrombocytopenia.

Acitretin may be used in monotherapy or combination with UVB or PUVA. It may be considered first line for palmoplantar psoriasis and erythrodermic psoriasis. Dosing is 10-25 mg daily or 0.25 mg/kg/day for erythrodermic patients Expect 2 months for full effect to be appreciated at optimal dose. Monitor: baseline lipids and LFTs; follow-up 2-4 weeks after use, then every 3 months Contraindications for acitretin include pregnancy, breast-feeding, and woman of childbearing potential who may get pregnant within 3 years after discontinuing acitretin (length of time remaining in system). Monitor for dyslipidemia.

Cyclosporine works rapidly and is efficacious for severe psoriasis or erythrodermic psoriasis. This medication should be used as a bridging and short-term therapy for 3-4 months at a time. Dosing is 0.5-5 g/kg/day divided into two daily doses. Expect rapid response within 1-2 weeks. Monitor baseline blood pressure, CMP, CBC, LFTs, lipid panel, Mg, and uric acid, and then follow-up with all labs every 2 weeks for 2 weeks, then every month. Adverse effects include impaired renal function, hypertension, concern for lymphoma, and potential for cutaneous malignancies.

Biologics

Among TNF-alpha inhibitors, infliximab has thhe fastest onset of action followed by adalimumab, and then etanercept. Caution should be used in starting and stopping these agents in a single patient, as neutralizing antibodies can develop when used in this capacity, thus rendering a medication no longer useful. Monitoring bloodwork including baseline CBC, LFT, hepatitis B and C, HIV if indicated, and PPD or QuantiFERON gold test; CBC and CMP every 3-6 months thereafter and PPD or QuantiFERON gold test yearly thereafter. Time to efficacy is 12 weeks.

These agents are contraindicated for patients with multiple sclerosis or other demyelinating diseases. Use caution with those with first-degree relatives with multiple sclerosis, as they may have an increased risk of developing the disease; active infection, including tuberculosis; congestive heart failure with New York Heart Association class III or IV or ejection factor <50%.

Adalimumab dosage is 80 mg the first week, 40 mg the second week, then 40mg every other week (given subcutaneously) Etanercept: dosage is 50 mg twice weekly for 3 months, then 50 mg weekly (given subcutaneously). Infliximab dosage is 5 mg/kg dose infusion at weeks 0, 2, and 6, and then every 6-8 weeks (with adjustment in intervals as needed for intravenous infusion).

Patient Management

Because of the differential diagnosis of erythrodermic psoriasis, repeat biopsy may be necessary to ensure diagnosis if the expected response to therapy does not occur.

Depending on the severity and acuteness of presentation, hospitalization may be necessary to montior vital signs, electrolytes, fluid status, and management of infection. Identification and rapid treatment of infection is important in these patients as this may exacerbate erythrodermic psoriasis as well. Wound cultures, complete blood count (CBC), and blood cultures may be necessary.

When discussing and treating any patient with psoriasis, explain the natural history of psoriasis with the explanation that this a chronic condition that will not be cured but can be controlled and that therapies often need 3 months to determine efficacy. If patients are not tolerating therapy or do not respond within the expected period of time, then an alternate therapy should be sought. If patients develop arthritis, then a systemic medication should be considered to help with arthritis if the patient is not on one.

Patients should be monitored for any evidence of systemic infections, arthritis symptoms, underlying malignancies on a regular basis. Patients also should be counseled for heart healthy behaviors, smoking cessation or reduction in alcohol consumption, and screened for depression/anxiety. Patients should also be encouraged to maintain as close to an ideal body weight as is possible.

Depending on the medication that patients are on, they should be monitored as outlined above. All therapies have risks and benefits that need to be closely considered.

If patients are clear from their disease, then drug holidays may be considered, especially with treatments such as topical medicines, phototherapy, methotrexate, or acitretin. This is more difficult with systemic biologic therapies, as the likelihood of developing antibodies, leading to resistance occurs more frequently if the biologic agent is used periodically rather than continuously, rendering them ineffective.

Patients taking biologic and/or immunosuppressant medications should be periodically re-evaluated for development of new symptoms including infection and malignancy as well as arthritic symptoms. Do not use live vaccines while on these therapies. Yearly purified protein derivative (PPD) or QuantiFERON gold testing is necessary to check for tuberculous infection.

For patients on methotrexate, no alcohol consumption is the guideline. Wth respect to liver biopsy, in patients with risk factors earlier liver biopsy may be necessary. Delayed baseline liver biopsy after 2-6 months of therapy to establish medication efficacy and tolerability should be considered, with repeated liver biopsies after approximately 1 to 1.5 g of medication.

Unusual Clinical Scenarios to Consider in Patient Management

Pediatric population

Often topical therapies are sufficient to manage children's disease. Caution should be used with topical corticosteroids in order to prevent skin atrophy in these patients. For treatment-resistant or severe disease, systemic therapies can be considered. For older children, limited courses of phototherapy eliminate some of the side effects associated with using systemic immunosuppressants.

Methotrexate and cyclosporine have been used to safely control disease in children; close monitoring should be employed. Oral retinoids (acitretin and related compounds) have been used safely and successfully in children; long term exposure can lead to premature epiphyseal closure and impaired growth. It also is absolutely contraindicated in pregnancy and in reproductive years, unless contraception during and for 3 years after therapy cessation is employed. Biologic therapies are not approved for use in children, although etanercept has been the best studied for psoriasis in pediatric population with overall good safety and isolated cases of severe infection.

Pregnancy

During pregnancy, special care must be used due to potential teratogenic effects of commonly used treatments. Often, psoriasis may improve during pregnancy due to hormonal changes.

Category B: systemic biologic agents; however, there is a relative lack of data regarding the safety of these medications during pregnancy in patients with psoriasis

Narrow band UVB, broad band UVB: considered the safest treatment for severe psoriasis during pregnancy

Nursing mothers

Safest therapy is NBUVB

Topical corticosteroids and topical calcipotriene are also considered safe

Methotrexate is contraindicated

Male partners of females trying to get pregnant

Methotrexate is contraindicated as it can lead to oligospermia, although no fetal malformation has been demonstrated. Conception should be delayed for 3 months after methotrexate use.

Use of systemic retinoids: it is unknown if teratogenic risk extends to children of male partners treated with acitretin. It is felt there is minimal to no risk and it can be continued to be prescribed.

Hepatitis B

Methotrexate should not be prescribed due to hepatotoxicity.

Because hepatitis B reactivation has been observed in patients undergoing therapy with TNF alpha inhibitors, screening for hepatitis B should occur prior to initiation of therapy. In hepatitis B-positive individuals with inactive disease, referral to gastrointestinal/hepatology is important for co-management of their disease. Oftentimes, a course of antivirals for 2-4 weeks should be initiated prior to anti-TNF therapy.

Hepatitis C

Methotrexate should not be used due to hepatotoxicity.

There is a relative lack of data regarding treatment of psoriasis in patients with hepatitis C, but UVB phototherapy is felt to be safe in this setting and is considered first line therapy if feasible.

Etanercept may act as an adjuvant to standard antiviral therapy in treating hepatitis C. Adalimumab and infliximab have been less well studied, but probably may be utilized in this clinical setting as well.

Cyclosporine also may be a treatment option in this patient population as in vitro evidence suggests that cyclosporine suppresses the replication of the hepatitis C virus.

HIV

Primary treatment is that of underlying HIV itself with anti-retrovirals.

Phototherapy is considered a first line systemic agent for treatment of psoriasis in this patient population.

Topical therapies also should be used first-line, although they typically are of limited success given the extent of involvement in this patient population.

Acitretin is considered a second line systemic therapy; caution with hyperlipidemia with acitretin and other antiretrovirals should be used.

For more refractory and severe disease, extremely cautious use of systemic immunosuppressants such as methotrexate, cyclosporine, or biologic therapies may be considered with collaboration with infectious disease specialists; however, these should be rarely used.

(This article demonstrated that mutations in IL36RN may be seen in pustular psoriasis, strengthening the role of IL36RA in its pathogenesis, and may serve as an important therapeutic target with medications such as anakinra.)

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